InCl3-Catalyzed One-Pot Synthesis of Pyrrolo/Indolo- and Benzooxazepino-Fused Quinoxalines

In this paper, we describe an efficient InCl3-catalyzed two-component reaction of 1-(2-aminophenyl)pyrroles/indoles and 2-propargyloxybenzaldehydes for the direct synthesis of 12bH-benzo[6,7]1,4-oxazepino[4,5-a]pyrrolo/indolo[2,1-c]quinoxalines. This high atom- and step-economical one-pot process generates three new C/N–C bonds in a single synthetic operation, resulting in the formation of new six- and seven-membered heterocyclic rings. The easy availability of the starting materials, the use of the relatively inexpensive indium catalyst, and the good substrate scope are the salient features of this strategy. The proposed mechanistic pathway involves imine formation, two consecutive cyclizations via electrophilic aromatic substitution and nucleophilic addition reactions, and the H shift step.


■ INTRODUCTION
Quinoxalines, as an important class of heterocyclic molecules, are attractive structural leads in medicinal chemistry due to their capacity to provide biological responses against various diseases. 1In fact, quinoxalines, called also benzopyrazines, have been the focus of a large number of investigations for years in the design and synthesis of novel biologically active agents that exhibit remarkable biological activities. 2 Quinoxaline derivatives have been reported to possess a wide range of medicinal activities, including antibacterial, antidiabetic, antiinflammatory, antimicrobial, antithrombotic, antitumor, and antiviral, and various enzyme inhibitory and receptor antagonist properties. 3Among quinoxaline derivatives, pyrrolo-[1,2-a]quinoxalines and their partly hydrogenated derivatives, such as 4,5-dihydropyrrolo[1,2-a]quinoxalines, have received considerable attention since they are often found in the structures of many biologically active compounds and functional molecules. 4In recent years, pyrrolo[1,2-a]quinoxalines and derivatives have been extensively studied since they exhibit a plethora of biological activities, such as antifungal, 5 antileishmanial, 6 antiparasitic and antimalarial, 7 antimycobacterial, 8 anti-HCV and anti-HIV, 9 antituberculosis, 10 antiulcer, 11 and antiproliferative and anticancer properties. 12These compounds have also been reported as inhibitors of enzymes FAAH and MAGL 13 and human protein kinases CK2 and RAD51. 12In addition, they act as 5-HT 3 receptor agonists 14 and central dopamine, 15 cannabinoid type 1 , 16 and glucagon receptor antagonists. 17Moreover, they show fluorescent and nonlinear optical properties, which lead to their applications in fluorescent probes and optical devices. 18ome examples of the important pyrrolo[1,2-a]quinoxalines are given in Scheme 1a.
Over the years, numerous methods have been developed for the synthesis of pyrrolo[1,2-a]quinoxalines, and new variants continue to appear.Pyrrolo[1,2-a]quinoxalines are generally synthesized from pyrroles or quinoxalines or from the compounds that are not initially derivatives of pyrroles or quinoxalines. 4In this regard, 1-(2-aminophenyl)pyrrole (2-(1H-pyrrol-1-yl)aniline) (1) and derivatives have emerged as valuable substrates since their cyclocondensation with carbonyl compounds such as aldehydes and ketones provided a diverse array of pyrrolo[1,2-a]quinoxalines and/or their dihydro derivatives. 19Notably, the use of functionally substituted aldehydes and ketones in these reactions may lead to the formation of new heterocyclic systems.
Recently, hybrid molecules, in which two or more pharmacophores are combined together in one molecule, have garnered significant interest since they provide enhanced or unusual activities as compared to their individual counterparts. 42,43Notably, heterocyclic hybrid molecules have exhibited better specificity, patient compliance, and aptitude to overcome drug resistance and reduced side effects. 44An ever-continuing aspect of these studies is to find novel hybrid molecules that will provide a new mode of action for the treatment of a specific disease.In this regard, the combination of pyrrole/indole, quinoxaline, and 1,4-oxazepine units in one molecule may lead to the discovery of hybrid compounds with increased activity profile as compared to the parent compounds.

■ RESULTS AND DISCUSSION
Initially, we synthesized the starting materials according to known literature procedures (Scheme 3).CuI-catalyzed coupling of iodoaniline derivatives 11 with pyrrole/indole (12) in the presence of DMEDA afforded the corresponding 1-(2-aminophenyl)pyrroles/indoles 1. 48On the other hand, the S N 2 reaction of salicylaldehyde (2-hydroxybenzaldehyde) derivatives 13 with propargyl bromide (14) in the presence of K 2 CO 3 yielded 2-propargyloxybenzaldehydes 6. 49 For the identity of R groups and the yields of products 1 and 6, see Supporting Information.Subsequently, we made a short optimization study on the basis of our previous and ongoing studies (Table 1). 47,50We performed the reactions in the presence of a 2 mol % InCl 3 catalyst since InCl 3 is quite effective as a π-Lewis acid for the activation of alkyne moieties toward nucleophilic addition, which enables cyclization via carbon/nitrogen−carbon bond formation. 51In addition, it is moisture compatible and plays an important role in organic synthesis, 52 especially in the synthesis of heterocycles. 53Briefly, they may present exciting oppor-Table 2. Synthesis of 12bH-Benzo [6,7]1,4-oxazepino [4,5-a] tunities for the development of new approaches and strategies.Initially, we carried out the reaction of 1-(2-aminophenyl)pyrrole (1a) with 2-propargyloxybenzaldehyde (6a) in toluene by heating to reflux for 4 h, which yielded a new heterocyclic compound, namely, 12bH-benzo [6,7]1,4-oxazepino[4,5-a]pyrrolo[2,1-c]quinoxaline (10a) but in a low yield (26%) (Table 1, entry 1).However, the same reaction in p-xylene formed product 10a in a higher yield (68%) even in a shorter time (2 h) (Table 1, entry 2).Obviously, the higher reaction temperature resulted in a higher yield of product 10a.When the reaction was carried out for 8 and 12 h, the yield of the product increased slightly (70%) (Table 1, entries 3 and 4).On the other hand, the longer reaction time such as 24 h reduced the yield of the product somewhat (68%) (Table 1, entry 5).So, the generality of the reaction was demonstrated by refluxing p-xylene using 2 mol % InCl 3 as the catalyst, which was monitored by routine TLC analysis.
Having established the optimal reaction conditions, we turned our focus to investigate the scope and limitations of the methodology by employing a variety of 1-(2-aminophenyl)pyrroles/indoles 1 and 2-propargyloxybenzaldehydes 6 to access pyrrolo/indolo-and benzooxazepino-fused quinoxalines 10 (Table 2).All reactions proceeded smoothly and provided the expected products.Importantly, during the course of the reaction, three new C/N−C bonds were formed, which enabled the formation of new six-and seven-membered heterocyclic rings.Moreover, during the reaction, as it will be depicted in the mechanism of the reaction (Scheme 4), terminal alkyne carbon atom of 6 converted into a methyl carbon in the final product 10.Therefore, the presence of the methyl peaks at 1.82−2.01ppm in 1 H NMR spectra and 16.7− 17.4 ppm in 13 C NMR spectra is clearly indicative of the formation of 12bH-benzo [6,7]1,4-oxazepino[4,5-a]pyrrolo/ indolo[2,1-c]quinoxaline derivatives 10.Overall, we synthesized 10 derivatives of quinoxalines 10, the yields of which changed from 25 to 83%.Notably, the yields (47−83%) of pyrrolo-fused quinoxalines 10a−f were mostly higher than those (25−50%) of indolo-fused quinoxalines 10g−j.This might be the result of that in electrophilic aromatic substitution reactions; the 2-positions of pyrroles are clearly more reactive than the 2-positions of indoles owing to aromaticity concerns and resonance interactions.
A possible mechanism for the synthesis of pyrrolo/indoloand benzooxazepino-fused quinoxalines 10 is shown for the reaction between 1-(2-aminophenyl)pyrrole 1a and 2-propargyloxybenzaldehyde 6a in Scheme 4. After the formation of imine 15a, InCl 3 activates the imine functionality through intermediate 16a.This triggers the intramolecular cyclization through the electrophilic aromatic substitution reaction of the pyrrole moiety to afford intermediate 17a, which upon aromatization yields pyrroloquinoxaline 9a.Then, the coordination of the indium (III) to alkyne group generates in situ intermediate 18a, in which the unsaturated alkyne moiety is activated toward nucleophilic addition.Afterward, nucleophilic addition of the amine group to the alkyne moiety in 7-exo-dig manner constructs the seven-membered ring (i.e., 1,4-oxazepine ring) of intermediate 19a, which after subsequent deprotonation delivers heterocycle 20a.Finally, the InCl 3 -catalyzed 1,3-H shift produces pyrrolo-and benzooxazepino-fused quinoxaline 10a.

■ CONCLUSIONS
In summary, we have established an InCl 3 -catalyzed twocomponent reaction between 1-(2-aminophenyl)pyrroles/ indoles 1 and 2-propargyloxybenzaldehydes 6 for the synthesis of pyrrolo/indolo-and benzooxazepino-fused quinoxaline derivatives 10 in moderate to good yields (up to 83%).This operationally simple one-pot approach shows several advantages including high step-and atom-economy, generation of three new C/N−C bonds in a single synthetic process, good substrate scope, and the use of a relatively inexpensive indium catalyst.Mechanistically, the reaction proceeds via imine Scheme 4. Mechanism Proposed for the Formation of 12bH-Benzo [6,7]1,4-oxazepino [4,5-a]pyrrolo/indolo[2,1c]quinoxalines 10 formation, successive intramolecular cyclizations through electrophilic aromatic substitution and nucleophilic addition reactions, and the H shift sequence.Importantly, the practical utility of the developed strategy and the skeletal diversity of the synthesized heterocyclic frame may provide many new nitrogen-and oxygen-based heterocyclic hybrid systems for drug discovery and development, which may modulate the activity of many targets that have been beyond the horizon of traditional compounds.Further investigation of the mechanism, scope, and limitations of this methodology is currently underway and will be reported in due course.
■ EXPERIMENTAL SECTION General Information. 1 H and 13 C NMR spectra were obtained at 400 and 100 MHz, respectively.Chemical shifts are given in parts per million (ppm) relative to CDCl 3 (7.26ppm in 1 H NMR and 77.16 ppm in 13 C NMR).Coupling constants (J) were given in hertz (Hz), and spin multiplicities were depicted by the following symbols: s (singlet), d (doublet), t (triplet), q (quartet), and m (multiplet).Infrared (IR) spectra were recorded by using attenuated total reflection.Peaks diagnostic for major functional groups were listed in reciprocal centimeters (cm −1 ).Mass spectra (MS) and high-resolution MS (HRMS) were obtained using electrospray ionization (ESI) with micro-Tof; m/z values are reported (for each measurement, the mass scale was recalibrated with sodium formate clusters, and samples were dissolved and measured in MeOH or CH 3 CN).Flash chromatography was performed with "flash-grade" silica gel (230−400 mesh) in thick-walled glass columns.TLC was realized by commercially available 0.25 mm silica gel plates, and visualization was achieved with a short-wavelength UV lamp (254 nm).The relative proportions of solvents used in chromatography indicate the volume/ volume ratio.Unless otherwise stated, all commercially available reagents were used directly without purification.All solvents used in chromatography and reactions were distilled or dried properly for purity.The inert atmosphere was created using a slight positive pressure (ca.0.1 psi) of argon.All glassware was dried in an oven prior to use.
1-(2-Aminophenyl)pyrroles/indoles (pyrrole/indole-substituted anilines) 1 and o-propargyloxybenzaldehydes 6 were synthesized according to literature studies (see Supporting Information). 48,49eneral Procedure.Synthesis of Pyrrolo/Indolo-and Benzooxazepino-Fused Quinoxalines 10 (Table 2).The corresponding o-propargyloxybenzaldehyde 6 (0.5 mmol) was dissolved in p-xylene (10 mL), and the proper pyrrole/ indole-substituted aniline 1 (0.6 mmol) was added in one portion under argon.After the reaction mixture was stirred for half an hour, InCl 3 (0.01 mmol) was added.The resulting reaction mixture was then refluxed at 140 °C for approximately 2 h.(The progress of the reaction was monitored by routine TLC analysis.)After the reaction was over, p-xylene was removed under reduced pressure.Purification of the obtained crude product by flash column chromatography on silica gel using 19:1 hexane/ethyl acetate as the eluent afforded the corresponding quinoxaline derivative 10.